No admission is made that any reference constitutes prior art. A large range of therapeutic compounds is currently used in the treatment of conditions such as allergies, diarrhoea, migraine and other pain conditions, and in the treatment of congestive heart failure. These compounds include compounds with analgesic or related activities, such as anti-tussives, anti-depressants, local anaesthetics, anti-hypertensives, anti-asthmatics, anti-histamines, and anti-serotonins.
However, many of the therapeutic compounds of the types enumerated above have undesirable side-effects, such as the respiratory depression caused by opiates. In particular, many drugs which are useful for their action on the peripheral nervous system have undesirable effects in the central nervous system.
Thus opiates are the most powerful analgesics known, but their usefulness is greatly limited by their side-effects, including severe respiratory depression, and ability to induce addiction and physical dependence.
Despite intensive efforts to design analogues of morphine and related opioids which retain the analgesic activity, but which do not have a deleterious effect on the central nervous system and the bowel, success has been limited. We have attempted to modify the ability of biologically-active compounds to cross the blood-brain barrier by incorporating a highly polar group into the molecular structure. Thus we have shown that derivatives of the 2N atom of mianserin comprising a guanidino group show H1 and 5-hydroxytryptamine activity, but show no detectable activity in the central nervous system. In contrast, a compound in which the 2N atom of mianserin was substituted with a urea group still showed pronounced central nervous system activity (Jackson et al; Clin. Ex. Pharmacol. Physiol., 1992 19 17–23 and our U.S. Pat. No. 5,049,637).
In our International patent application No. PCT/AU00/00062 (WO99/38869), we showed that compounds obtained by linking a highly charged group to the tertiary nitrogen atom of a morphine-like opioid via a spacer group not only have reduced central side-effects, but retain activity at desired peripheral receptors. We believe that this is a result of the decreased lipophilicity of the compounds, and their resulting decreased ability to penetrate the blood-brain barrier. In particular, those compounds which show activities at opioid receptors retained broad analgesic activity, contrary to the previously accepted state of the art, which teaches that the analgesic effects of morphine-like opioids are mediated from the CNS. The selectivity of these compounds for peripheral opioid receptors not only makes them useful for the treatment of pain without sedative or addictive effects, but also may make them useful for treatment of AIDS and related immune deficiency diseases.
We have now surprisingly found that compounds of this general type in which one or both nitrogen atoms in the amidine or guanidine group are substituted with an aryl group have remarkably high analgesic activity, accompanied by reduced toxicity. These compounds also have the desired decreased ability to penetrate the blood-brain barrier.